4-Phenylbutyric Acid Reduces the Proliferation in Colon Cancer Cell Lines Through Modulating the Cell Cycle Regulatory Genes: An In Silico and In Vitro Approach

Abstract

Background

Endoplasmic reticulum stress (ER-stress) is recognized to have a major role in both the onset and progression of various diseases, including cancer. Therefore, much research has focused on developing chemical chaperones or small compounds to reduce ER-stress in various disease conditions.

Aim

The present study investigates the effects of 4-phenylbutyric acid (4-PBA) on the modulation of proliferation and inflammatory responses in colon cancer cell lines by possibly regulating ER-stress-related protein expression.

Materials

Molecular docking and molecular dynamics simulations were performed to determine the binding affinity of 4-PBA with ER-stress-regulating proteins (IRE1-α, PDI, GRP78, PERK, NRF2). To validate our hypothesis, the expression levels for ER-stress-regulating genes (GRP78, XBP1, ATF6, PDI, PERK), pro-inflammatory genes (CXCL12, MCP1, COX2, CCR5), and the cell-cycle regulatory genes (CDK6, CCND1), as well as the inflammatory proteins (IL-6, IFN-γ, and CXCL10) expression and level of catalase and ROS, were studied in colon cancer cell lines before and after treatment of different concentrations of 4-PBA.

Results

In silico analysis showed that 4-PBA could bind with IRE1-α and PERK ER-stress proteins strongly, with the binding energy of −6.8 and −6.5 Kcal/mol. Treatment with 4-PBA showed downregulation of pro-inflammatory genes, along with the ER-stress and cell-cycle regulatory genes. The reduced expression of pro-inflammatory proteins along with ROS and subsequent elevation in catalase levels by 4-PBA in colon cancer cell lines indicates a correlation between ER-stress and inflammatory response.

Conclusion

The study revealed that 4-PBA has anti-inflammatory and anticarcinogenic properties, providing new avenues for future research.